During fiscal year 2007 we accomplished the following:[unreadable] (1) We identified an unusual form of cell death of primary B lymphocytes in response to a single pulse of antigen receptor signaling. This stimulus induced the normal pattern of NF-B induction, and did not activate the pro-apoptotic protein Bim that is usually induced by continuous anti-Ig signaling. Both these characteristics should favor cell survival, yet these cells die at significantly higher levels than untreated cells, or cells treated continuously with anti-immunoglobulin.[unreadable] [unreadable] (2) We found that c-Rel-deficient B cells are less prone to passive cell death in ex-vivo cultures. Because this form of cell death is prevented by the survival cytokine BLys/BAFF, it suggests a connection between canonical (p65 and c-Rel-dependent) and non-canonical (p52/Rel B-dependent) pathways.[unreadable] [unreadable] (3) We initiated experiments to study the relationship of protein nitrosylation (as one form of oxidative stress) and NF-B function. A possible role of nitrosylation on cell death in immune cells is suggested by one published paper indicating that post-activation passive cell death of CD4+ T cells is reduced in the absence of inducible nitric oxide synthase (iNOS). To substantiate this observation and extend it in a mechanistic direction, we generated iNOS/c-Rel double-deficient mice and analyzed the induction of iNOS protein systhesis in activated CD4+ T cells. Ongoing studies are directed at the effects of iNOS activation, or inhibition, on cytokine production and cell death.